Mapping the frontier orbital energies of imidazolium-based cations using machine learning.

The knowledge of the frontier orbital, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), energies is vital for studying chemical and electrochemical stability of compounds, their corrosion inhibition potential, reactivity, etc. Density functional theory (DFT) calculations provide a direct route to estimate these energies either in the gas-phase or condensed phase. However, the application of DFT methods becomes computationally intensive when hundreds of thousands of compounds are to be screened. Such is the case when all the isomers for the 1-alkyl-3-alkylimidazolium cation [CnCmim]+ (n = 1-10, m = 1-10) are considered. Enumerating the isomer space of [CnCmim]+ yields close to 386 000 cation structures. Calculating frontier orbital energies for each would be computationally very expensive and time-consuming using DFT. In this article, we develop a machine learning model based on the extreme gradient boosting method using a small subset of the isomer space and predict the HOMO and LUMO energies. Using the model, the HOMO energies are predicted with a mean absolute error (MAE) of 0.4 eV and the LUMO energies are predicted with a MAE of 0.2 eV. Inferences are also drawn on the type of the descriptors deemed important for the HOMO and LUMO energy estimates. Application of the machine learning model results in a drastic reduction in computational time required for such calculations.

Elucidating the effect of the ionic liquid type and alkyl chain length on the stability of ionic liquid-iron porphyrin complexes.

The present study is motivated by the long-term objective of understanding how ionic liquids are biodegraded by cytochrome P450, which contains iron porphyrin (FeP) serving as the catalytic center. To this end, the current study is designed to elucidate the impact of types and conformations of ionic liquids on the binding energy with FeP, the key interactions that stabilize the ionic liquid-FeP complex, and how the electron uptake ability of FeP is altered in the presence of ionic liquids. Four classes of ionic liquids are considered: 1-alkyl-3-methylimidazolium, 1-alkyl-pyridinium, 1-alkylsulfonium, and N-methyl-N-alkylpyrrolidinium. The influence of linear alkyl chains of ethyl, butyl, hexyl, octyl, and decyl is examined on the favorable binding modes with FeP, considering two widely different conformations: tail up and tail down with respect to FeP. Electronic structure calculations are performed at the M06 level of theory with the 6-31G(d,p) basis set for C, H, and N atoms, while the Lanl2DZ basis set is employed for Fe. Donor-acceptor interactions contributing to the binding of ionic liquids to FeP are unraveled through the natural bond orbital analysis. The results from this study indicate that the binding energies are dependent not only on the class of ionic liquids but also on the conformations presented to FeP. The propensity of FeP to acquire an electron is significantly enhanced in the presence of ionic liquid cations, irrespective of the type and the alkyl chain length.

Insight into conformationally-dependent binding of 1-n-alkyl-3-methylimidazolium cations to porphyrin molecules using quantum mechanical calculations.

The first step in the biodegradation of imidazolium-based ionic liquids involves the insertion of the -OH group into the alkyl side chain, and it is believed to be triggered by cytochrome P450. However, at present, there is a lack of fundamental understanding of why the hydroxylation process is observed only for longer alkyl chain analogues. As the initial step of the hydroxylation reaction involves the ionic liquid binding to Fe-porphyrin (FeP) - the catalytic center of cytochrome P450, the orientation of ionic liquids presented to FeP is expected to play a crucial role in eventual hydroxylation of the alkyl side chain. In order to elucidate the chain-length dependent binding preferences exhibited by the homologous series of 1-n-alkyl-3-methylimidazolium (n = 2, 4, 6, 8, and 10) [Cnmim]+ cations, a quantum mechanical treatment of the cations in the presence of free base porphyrin (FBP) and FeP is carried out at the B3LYP-D2 and M06 levels. The binding energy of different complexes with FBP and FeP is investigated by considering three vastly different starting relative orientations of the cations with respect to FBP and FeP: tail down, tail up, and interplanar. Our calculations of binding energies reveal that the cation orientations initiated from the tail down conformations (alkyl chain facing the porphyrin molecules) are progressively destabilized as the alkyl chain length increases. The decomposition of the binding energies into various energetic contributions shows that the interaction energy between the cations and porphyrin molecules varies with the cation geometries presented to porphyrin molecules and is the primary determinant of the magnitude of the binding energies. We further demonstrate that the propensity of the cation-FeP complexes to acquire an electron, the next step in the hydroxylation reaction cycle upon substrate binding, is favored independent of the cations and conformations, suggesting that this step is not the reason for the low biodegradability of short alkyl chain bearing cations. Furthermore, the weaker binding of the ionic liquid to FeP is anticipated to facilitate dioxygen binding to FeP, the step following the electron transfer reaction. Overall, the results of the present calculations indicate that the destabilization of the tail down conformations relative to the other two conformations correlates with the experimental results of the chain length-dependent biodegradation of imidazolium-based ionic liquids.

Cassandra: An open source Monte Carlo package for molecular simulation.

Cassandra is an open source atomistic Monte Carlo software package that is effective in simulating the thermodynamic properties of fluids and solids. The different features and algorithms used in Cassandra are described, along with implementation details and theoretical underpinnings to various methods used. Benchmark and example calculations are shown, and information on how users can obtain the package and contribute to it are provided. © 2017 Wiley Periodicals, Inc.

Molecular dynamics simulation study of the association of lidocainium docusate and its derivatives in aqueous solution.

Ionic liquid active pharmaceutical ingredients (IL APIs) are novel materials in which the ions themselves are APIs, but the pure salt is a liquid under ambient conditions. It has been found that IL APIs can have superior performance relative to their conventional salt analogues, but the mechanism for this is unclear. We have used molecular simulations to estimate the aqueous phase association constants of the IL API lidocainium docusate and their sodium and chloride counterparts. Lidocainium is the cationic form of lidocaine, a local anesthetic, while the docusate anion is an emollient. From strongest to weakest, the calculated association constants are 10.1 M(-1) (lidocainium docusate); 0.77 M(-1) (sodium chloride); 0.086 M(-1) (sodium docusate); and 0.065 M(-1) (lidocainium chloride). These results suggest that the experimentally observed enhanced efficacy of lidocainium docusate relative to the traditional drug formulation as a lidocaine hydrochloride salt could result from association of the ions in aqueous solution and at the cell membrane, leading to a synergistic activity effect.

Amphiphilic interactions of ionic liquids with lipid biomembranes: a molecular simulation study.

Current bottlenecks in the large-scale commercial use of many ionic liquids (ILs) include their high costs, low biodegradability, and often unknown toxicities. As a proactive effort to better understand the molecular mechanisms of ionic liquid toxicities, the work herein presents a comprehensive molecular simulation study on the interactions of 1-n-alkyl-3-methylimidazolium-based ILs with a phosphatidylcholine (PC) lipid bilayer. We explore the effects of increasing alkyl chain length (n = 4, 8, and 12) in the cation and anion hydrophobicity on the interactions with the lipid bilayer. Bulk atomistic molecular dynamics (MD) simulations performed at millimolar (mM) IL concentrations show spontaneous insertion of cations into the lipid bilayer regardless of the alkyl chain length and a favorable orientational preference once a cation is inserted. Cations also exhibit the ability to "flip" inside the lipid bilayer (as is common for amphiphiles) if partially inserted with an unfavorable orientation. Moreover, structural analysis of the lipid bilayer show that cationic insertion induces roughening of the bilayer surface, which may be a precursor to bilayer disruption. To overcome the limitation in the timescale of our simulations, free energies for a single IL cation and anion insertion have been determined based on potential of mean force calculations. These results show a decrease in free energy in response to both short and long alkyl chain IL cation insertion, and likewise for a single hydrophobic anion insertion, but an increase in free energy for the insertion of a hydrophilic chloride anion. Both bulk MD simulations and free energy calculations suggest that toxicity mechanisms toward biological systems are likely caused by ILs behaving as ionic surfactants. [Yoo et al., Soft Matter, 2014].

Effect of K+ Force Fields on Ionic Conductivity and Charge Dynamics of KOH in Ethylene Glycol.

Predicting ionic conductivity is crucial for developing efficient electrolytes for energy storage and conversion and other electrochemical applications. An accurate estimate of ionic conductivity requires understanding complex ion-ion and ion-solvent interactions governing the charge transport at the molecular level. Molecular simulations can provide key insights into the spatial and temporal behavior of electrolyte constituents. However, such insights depend on the ability of force fields to describe the underlying phenomena. In this work, molecular dynamics simulations were leveraged to delineate the impact of force field parameters on ionic conductivity predictions of potassium hydroxide (KOH) in ethylene glycol (EG). Four different force fields were used to represent the K+ ion. Diffusion-based Nernst-Einstein and correlation-based Einstein approaches were implemented to estimate the ionic conductivity, and the predicted values were compared with experimental measurements. The physical aspects, including ion-aggregation, charge distribution, cluster correlation, and cluster dynamics, were also examined. A force field was identified that provides reasonably accurate Einstein conductivity values and a physically coherent representation of the electrolyte at the molecular level.

Role of Intermolecular Interactions in Deep Eutectic Solvents for CO2 Capture: Vibrational Spectroscopy and Quantum Chemical Studies.

Recent research and reviews on CO2 capture methods, along with advancements in industry, have highlighted high costs and energy-intensive nature as the primary limitations of conventional direct air capture and storage (DACS) methods. In response to these challenges, deep eutectic solvents (DESs) have emerged as promising absorbents due to their scalability, selectivity, and lower environmental impact compared to other absorbents. However, the molecular origins of their enhanced thermal stability and selectivity for DAC applications have not been explored before. Therefore, the current study focuses on a comprehensive investigation into the molecular interactions within an alkaline DES composed of potassium hydroxide (KOH) and ethylene glycol (EG). Combining Fourier transform infrared (FT-IR) and quantum chemical calculations, the study reports structural changes and intermolecular interactions induced in EG upon addition of KOH and its implications on CO2 capture. Experimental and computational spectroscopic studies confirm the presence of noncovalent interactions (hydrogen bonds) within both EG and the KOH-EG system and point to the aggregation of ions at higher KOH concentrations. Additionally, molecular electrostatic potential (MESP) surface analysis, natural bond orbital (NBO) analysis, quantum theory of atoms-in-molecules (QTAIM) analysis, and reduced density gradient-noncovalent interaction (RDG-NCI) plot analysis elucidate changes in polarizability, charge distribution, hydrogen bond types, noncovalent interactions, and interaction strengths, respectively. Evaluation of explicit and hybrid models assesses their effectiveness in representing intermolecular interactions. This research enhances our understanding of molecular interactions in the KOH-EG system, which are essential for both the absorption and desorption of CO2. The study also aids in predicting and selecting DES components, optimizing their ratios with salts, and fine-tuning the properties of similar solvents and salts for enhanced CO2 capture efficiency.

Aripiprazole versus olanzapine in the treatment of schizophrenia: a clinical study from India.

OBJECTIVE: The aim of the study was to compare efficacy and tolerability of aripiprazole with olanzapine in the short-term treatment of schizophrenia in an Indian population. METHOD: This was a randomized double-blind controlled study comparing aripiprazole and olanzapine in the treatment of individuals with schizophrenia in an inpatient clinical setting. Sixty subjects between 18 and 65 years of age, who fulfilled the ICD-10 criteria for schizophrenia, were enrolled. Patients' detailed demographic and clinical evaluation was conducted and they were administered efficacy assessment scales (BPRS, PANSS) and safety assessments scale (Simpson Angus Scale, UKU side effect rating scale) at regular intervals of 1 week each throughout the study. The laboratory tests (complete haemogram, electrocardiogram (ECG), lipid profile, liver and renal function tests) were conducted at baseline and after 1-week intervals until 6 weeks of treatment. The patients were randomly allocated to receive either aripiprazole or olanzapine. RESULTS: Both aripiprazole and olanzapine led to significant reductions on BPRS and PANSS total score over a period of 6 weeks. Weight gain was observed more frequently in the olanzapine-treated group (22.20%) as compared to aripiprazole (7.70%). More patients in the aripiprazole treatment group required comedications (trihexiphenidyl and lorazepam) than olanzapine recipients. CONCLUSION: This study demonstrates that aripiprazole is equally efficacious as olanzapine in the treatment of schizophrenia. Aripiprazole has a more benign side effect profile (weight gain, blood sugar level, lipid profile) as compared to olanzapine in the short-term treatment of schizophrenia. This study is the first in an Indian population to have compared aripiprazole and olanzapine.

A comparison of the solvation thermodynamics of amino acid analogues in water, 1-octanol and 1-n-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquids by molecular simulation.

A computational approach is developed to quantitatively study the solvation thermodynamics of amino acid analogues in ionic liquids via molecular simulation. The solvation thermodynamics of amino acid analogues in ionic liquids is important for an understanding of protein-ionic liquid interactions, shedding insight into the structure and solubility of proteins, and the activity of enzymes in ionic liquids. This information is additionally key to developing novel extraction processes. As a result of the challenge of quantitatively describing the solvation behavior of ionic liquids, a key outcome of the present study is the development of a "hydrophobicity" scale to quantitatively describe the amino acid analogues. The scale allows one to separate the results of both the hydrophobic and hydrophillic analogues, simplifying an understanding of the observed trends. Equipped with the proposed hydrophobicity scale, one needs only perform conventional solvation free energy calculations of the amino acid analogues in the ionic liquids of interest. The necessary simulation tools are available in most open-source simulation software, facilitating the adoption of this approach by the simulation community at large. We have studied the case of varying the cation alkyl-chain length of a 1-n-alkyl-3-methylimidazolium cation paired with the bis(trifluoromethylsulfonyl)imide anion. The findings suggest that a judicious selection of both the cation and anion could potentially lead to a solvent for which the amino acid analogues have an affinity far greater than that for both water and a non-polar reference solvent.

Water coordination structures and the excess free energy of the liquid.

We assess the contribution of each coordination state to the hydration free energy of a distinguished water molecule, the solute water. We define a coordination sphere, the inner-shell, and separate the hydration free energy into packing, outer-shell, and local, solute-specific (chemical) contributions. The coordination state is defined by the number of solvent water molecules within the coordination sphere. The packing term accounts for the free energy of creating a solute-free coordination sphere in the liquid. The outer-shell contribution accounts for the interaction of the solute with the fluid outside the coordination sphere and it is accurately described by a Gaussian model of hydration for coordination radii greater than the minimum of the oxygen-oxygen pair-correlation function: theory helps identify the length scale to parse chemical contributions from bulk, nonspecific contributions. The chemical contribution is recast as a sum over coordination states. The nth term in this sum is given by the probability p(n) of observing n water molecules inside the coordination sphere in the absence of the solute water times a factor accounting for the free energy, W(n), of forming an n-water cluster around the solute. The p(n) factors thus reflect the intrinsic properties of the solvent while W(n) accounts for the interaction between the solute and inner-shell solvent ligands. We monitor the chemical contribution to the hydration free energy by progressively adding solvent ligands to the inner-shell and find that four-water molecules are needed to fully account for the chemical term. For a chemically meaningful coordination radius, we find that W(4) ≈ W(1) and thus the interaction contribution is principally accounted for by the free energy for forming a one-water cluster, and intrinsic occupancy factors alone account for over half of the chemical contribution. Our study emphasizes the need to acknowledge the intrinsic solvent properties in interpreting the hydration structure of any solute, with particular care in cases where the solute-solvent interaction strength is similar to that between the solvent molecules.

A general and efficient Monte Carlo method for sampling intramolecular degrees of freedom of branched and cyclic molecules.

A simple and easily implemented Monte Carlo algorithm is described which enables configurational-bias sampling of molecules containing branch points and rings with endocyclic and exocyclic atoms. The method overcomes well-known problems associated with sequential configurational-bias sampling methods. A "reservoir" or "library" of fragments are generated with known probability distributions dependent on stiff intramolecular degrees of freedom. Configurational-bias moves assemble the fragments into whole molecules using the energy associated with the remaining degrees of freedom. The methods for generating the fragments are validated on models of propane, isobutane, neopentane, cyclohexane, and methylcyclohexane. It is shown how the sampling method is implemented in the Gibbs ensemble, and validation studies are performed in which the liquid coexistence curves of propane, isobutane, and 2,2-dimethylhexane are computed and shown to agree with accepted values. The method is general and can be used to sample conformational space for molecules of arbitrary complexity in both open and closed statistical mechanical ensembles.

A method for computing the solubility limit of solids: application to sodium chloride in water and alcohols.

We present an adaptable method to compute the solubility limit of solids by molecular simulation, which avoids the difficulty of reference state calculations. In this way, the method is highly adaptable to molecules of complex topology. Results are shown for solubility calculations of sodium chloride in water and light alcohols at atmospheric conditions. The pseudosupercritical path integration method is used to calculate the free energy of the solid and gives results that are in good agreement with previous studies that reference the Einstein crystal. For the solution phase calculations, the self-adaptive Wang-Landau transition-matrix Monte Carlo method is used within the context of an expanded isothermal-isobaric ensemble. The method shows rapid convergence properties and the uncertainty in the calculated chemical potential was 1% or less for all cases. The present study underpredicts the solubility limit of sodium chloride in water, suggesting a shortcoming of the molecular models. Importantly, the proper trend for the chemical potential in various solvents was captured, suggesting that relative solubilities can be computed by the method.

Macroscopic Differentiators for Microscopic Structural Nonideality in Binary Ionic Liquid Mixtures.

Combining two ionic liquids to form a binary ionic liquid mixture is a simple yet effective strategy to not only expand the number of ionic liquids but also precisely control various physicochemical properties of resultant ionic liquid mixtures. From a fundamental thermodynamic point of view, it is not entirely clear whether such mixtures can be classified as ideal solutions. Given a large number of binary ionic liquid mixtures that emerge, the ability to predict the presence of nonideality in such mixtures a priori without the need for experimentation or molecular simulation-based calculations is immensely valuable for their rational design. In this research report, we demonstrate that the difference in the molar volumes (ΔV) of the pure ionic liquids and the difference in the hydrogen-bonding ability of anions (Δß) are the primary determinants of nonideal behavior of binary ionic liquid mixtures containing a common cation and two anions. Our conclusion is derived from a comparison of microscopic structural properties expressed in terms of radial, spatial, and angular distributions for binary mixtures and those of the corresponding pure ionic liquids. Molecular dynamics simulations of 16 binary ionic liquid mixtures, containing a common cation 1-n-butyl-3-methylimidazolium [C4mim]+ and combinations of (less basic) fluorinated {trifluoromethylacetate [TFA]-, trifluoromethanesulfonate [TFS]-, bis(trifluoromethanesulfonyl)imide [NTf2]-, and tris (pentafluoroethyl) trifluorophosphate [eFAP]-} versus (more basic) nonfluorinated {chloride Cl-, acetate [OAC]-, methylsulfate [MeSO4]-, and dimethylphosphate [Me2PO4]-} anions, were conducted. The large number of binary ionic liquid mixtures examined here enabled us to span a broad range of ΔV and Δß values. The results indicate that binary mixtures of two ionic liquids for which ΔV > 60 cm3/mol and Δß > 0.4 are expected to be microscopically nonideal. On the other hand, ΔV < 60 cm3/mol and Δß < 0.4 will lead to molecular structures that are not differentiated from those of their pure ionic liquid counterparts.

Mesoscale Organization and Dynamics in Binary Ionic Liquid Mixtures.

The impact of mesoscale organization on dynamics and ion transport in binary ionic liquid mixtures is investigated by broad-band dielectric spectroscopy, dynamic-mechanical spectroscopy, X-ray scattering, and molecular dynamics simulations. The mixtures are found to form distinct liquids with macroscopic properties that significantly deviate from weighted contributions of the neat components. For instance, it is shown that the mesoscale morphologies in ionic liquids can be tuned by mixing to enhance the static dielectric permittivity of the resulting liquid by as high as 100% relative to the neat ionic liquid components. This enhancement is attributed to the intricate role of interfacial dynamics associated with the changes in the mesoscopic aggregate morphologies in these systems. These results demonstrate the potential to design the physicochemical properties of ionic liquids through control of solvophobic aggregation.

LC-UV-PDA and LC-MS studies to characterize degradation products of glimepiride.

Degradation products of glimepiride formed under different forced conditions have been characterized through LC-UV-PDA and LC-MS studies. Glimepiride was subjected to forced decomposition under the conditions of hydrolysis, oxidation, dry heat and photolysis, in accordance with the ICH guideline Q1A(R2). The reaction solutions were chromatographed on reversed phase C8 (150 mm x 4.6mm i.d., 5 microm) analytical column. In total, five degradation products (I-V) were formed under various conditions. The drug degraded to products II and V under acid and neutral hydrolytic conditions while products I, III and IV were formed under the alkaline conditions. The products II and V were also observed on exposure of drug to peroxide. No additional degradation product was shown up under photolytic conditions. All the products, except I, could be characterized through LC-PDA analyses and study of MS fragmentation pattern in both +ESI and -ESI modes. Product I could not be identified, as it did not ionize under MS conditions. The products II, III and V matched, respectively, to impurity B (glimepiride sulfonamide), impurity J and impurity C (glimepiride urethane) listed in European Pharmacopoeia. The product IV was a new degradation product, characterized as [[4-[2-(N-carbamoyl)aminoethyl]phenyl]sulfonyl]-3-trans-(4-methylcyclohexyl) urea. The degradation pathway of the drug to products II-V is proposed, which is yet unreported.

LC and LC-MS study on establishment of degradation pathway of glipizide under forced decomposition conditions.

Forced degradation studies on glipizide are conducted under the conditions of hydrolysis, oxidation, photolysis, and dry heat. The solutions are subjected to liquid chromatographic (LC) investigations to establish the number of products formed in each condition. The degradation products are characterized through isolation and subsequent NMR, IR, and MS spectral analyses, or through LC-mass spectrometry (MS) fragmentation pattern study. The drug is shown to degrade in 0.1M HCl at 85 degrees C to two products: 5-methyl-N-[2-(4-sulphamoylphenyl)ethyl]pyrazine-2-carboxamide (II) and methyl N-[4-[2-{(5-methyl-2-pyrazinoyl)amino}ethyl] phenyl]sulfonyl carbamate (III). The latter, a methyl ester, is formed only in the presence of methanol (used as a solubilizer), and does not appear on use of acetonitrile. III is shown to convert to II on continued heating in acid. The drug degrades slowly in water at the same temperature, and both II and III could be seen in the chromatograms until the end of the study. The heating of the drug in alkali (0.1M NaOH) at 85 degrees C yields 5-methyl-2-pyrazinecarboxylic acid (IV), along with a small quantity of 4-(2-aminoethyl) benzenesulfonamide (I). On extended heating in the same condition, a new product, 4-(2-aminoethyl)-N,N-bis[(cyclohexylamino)carbonyl] benzenesulfonamide (VI) is formed in small quantities. At the lower temperature of 40 degrees C, the drug converts under each hydrolytic condition and in both the absence and presence of light to products II, III, or IV, along with a new product, 1-cyclohexyl-3-[[4-(2aminoethyl)phenyl] sulfonyl]urea (V). The light catalyzes formation of V, and it is formed until one or two weeks, after which its level decreases. The drug remains stable in 30% H2O2, except that products II and III appear as small peaks due to acidic character of the peroxide solution. Also, the drug remains unaffected in solid state under thermal and photolytic stress conditions. Based on the results, a more complete picture on degradation pathway of the drug is obtained, highlighting a clear advantage of the approach suggested by International Conference on Harmonization.

Globular, Sponge-like to Layer-like Morphological Transition in 1-n-Alkyl-3-methylimidazolium Octylsulfate Ionic Liquid Homologous Series.

Segregation of polar and nonpolar domains in ionic liquids for which either the cation or anion is responsible for inducing nonpolar domains is well understood. On the other hand, information regarding the nanoscale heterogeneities originating due to the presence of nonpolar content on both the ions is rudimentary at this point. The present contribution is aimed at addressing this question and focuses on a molecular dynamics simulation study to probe nanoscale structural and aggregation features of the 1-n-alkyl-3-methylimidazolium [Cnmim] octylsulfate [C8SO4] ionic liquid homologous series (n = 2, 4, 6, 8, 10, and 12). The objective of this work is to determine the effect of increasing alkyl chain length in the cation on nonpolar domain formation, especially when the alkyl chain lengths from both the ions participate in defining such domains. The results indicate that all the ionic liquids form nonpolar domains, morphology of which gradually changes from globular, sponge-like to layer-like structure with increase in the cationic alkyl chain length. The length of the nonpolar domains calculated from the total structure factor for [C10mim][C8SO4] is considerably higher than that reported for other imidazolium-based ionic liquid containing smaller anions. The structure factor for [C12mim][C8SO4] ionic liquid contains multiple intermediate peaks separating the charge alternation peak and pre-peak, which points to nonpolar domains of varying lengths, an observation that remains to be validated. Analysis of the heterogeneous order parameters and orientational correlation functions of the alkyl chains further suggests an increase in the spatial heterogeneity and long-range order along the homologous series. The origin of rich diversity of structures obtained by introducing nonpolar content on both the ions is discussed.

Molecular Origins of the Apparent Ideal CO2 Solubilities in Binary Ionic Liquid Mixtures.

Molecular dynamics (MD) simulations were conducted to investigate the variation of Henry's constant of CO2 in two binary ionic liquid mixtures. One of the mixtures is formed by pairing the cation 1- n-butyl-3-methylimidazolium [C4mim]+ with chloride Cl- and methylsulfate [MeSO4]-, whereas the other binary ionic liquid mixture contains [C4mim]+ in combination with the anions Cl- and bis(trifluoromethanesulfonyl)imide [NTf2]-. In order to provide a microscopic understanding of the behavior of the Henry's constant with the anion composition, MD simulations of ionic liquid mixtures with and without CO2 saturation were performed at 353 K and 10 bar. Our calculations indicate that the Henry's constant for CO2 follows a highly nonlinear, although expected based on ideal solubility, trend with respect to the increasing concentration of Cl- in [C4mim]Cl x[NTf2]1- x, whereas the Henry's constant is almost independent of the anion composition in the [C4mim]Cl x[MeSO4]1- x system. Structural analyses presented in terms of radial, spatial, and angular distribution functions point to significant structural reorganization of the anions around cations in the [C4mim]Cl x[NTf2]1- x system. Because of the weakly coordinating ability of the [NTf2]- anion with the cation, the [NTf2]- anion is displaced from the equatorial plane of the imidazolium ring and occupies positions above and below the ring, enabling enhanced CO2-[NTf2]- association. The rearrangement also weakens the cation π-π interactions, resulting in the formation of increased local free volume aiding CO2 accommodation. On the contrary, such structural transitions are absent in the [C4mim]Cl x[MeSO4]1- x mixture system.

LC and LC-MS study of stress decomposition behaviour of isoniazid and establishment of validated stability-indicating assay method.

Isoniazid was subjected to different ICH prescribed stress conditions of thermal stress, hydrolysis, oxidation and photolysis. The drug was stable to dry heat (50 and 60 degrees C). It showed extensive decomposition under hydrolytic conditions, while it was only moderately sensitive to oxidation stress. The solid drug turned intense yellow on exposure to light under accelerated conditions of temperature (40 degrees C) and humidity (75% RH). In total, three major degradation products were detected by LC. For establishment of stability-indicating assay, the reaction solutions in which different degradation products were formed were mixed, and the separation was optimized by varying the LC conditions. An acceptable separation was achieved using a C-18 column and a mobile phase comprising of water:acetonitrile (96:4, v/v), with flow rate and detection wavelength being 0.5 ml min(-1) and 254 nm, respectively. The degradation products appeared at relative retention times (RR(T)) of 0.71, 1.34 and 4.22. The validation studies established a linear response of the drug at concentrations between 50 and 1000 microg ml(-1). The mean values (+/-R.S.D.) of slope, intercept and correlation coefficient were 35,199 (+/-0.88), 114,310 (+/-4.70) and 0.9998 (+/-0.01), respectively. The mean R.S.D. values for intra- and inter-day precision were 0.24 and 0.90, respectively. The recovery of the drug ranged between 99.42 and 100.58%, when it was spiked to a mixture of solutions in which sufficient degradation was observed. The specificity was established through peak purity testing using a photodiode array detector. The method worked well on application to marketed formulation of isoniazid, and a fixed-dose combination containing isoniazid and ethambutol HCl. It was even extendable to LC-MS studies, which were carried out to identify the three degradation products. The m/z values of the peaks at RR(T) 0.71 and RR(T) 1.34 matched with isonicotinic acid and isonicotinamide, respectively. The product appearing at RR(T) 4.22 was isolated using preparative LC-MS, and turned out to be a yellow compound that was identified as isonicotinic acid N'-(pyridyl-4-carbonyl)-hydrazide based on mass, FTIR and (1)H/(13)C NMR spectral data. The same was indicated to be responsible for discolouration of isoniazid bulk drug substance and formulations, which is a familiar problem. The mechanism of formation of the said compound is outlined.